Enlarged-hetero-ring prostacyclin analogs

ABSTRACT

Prostaglandin (PG 1 ) derivatives having (1) a 6-keto feature, together with a 9-deoxy-9-hydroxymethyl feature for example ##STR1## or (2) a 9-deoxy-6,9-epoxymethano feature together with a 5-halo or 6-hydroxy feature, for example ##STR2## or a 5,6-didehydro feature, for example in an enol ether of the formula ##STR3## said derivatives having pharmacological activity. Processes for preparing them and the appropriate intermediates are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of then copending application Ser. No.819,941 filed July 28, 1977, now issued as U.S. Pat. No. 4,124,599,which was a continuation-in-part of then copending application Ser. No.725,547 filed Sept. 22, 1976, since abandoned, which was acontinuation-in-part of then copending application Ser. No. 716,777filed Aug. 23, 1976, since abandoned.

INCORPORATION BY REFERENCE

The essential material for this application, including the background ofthe invention, the disclosure of the invention, and the description ofthe preferred embodiments, including Preparations and Examples, isincorporated by reference from issued U.S. Pat. No. 4,124,599, under theprovisions of M.P.E.P. 608.01(p).

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin derivatives and to a process forpreparing them.

The prostaglandins and analogs are well-known organic compounds derivedfrom prostanoic acid which has the following structure and atomnumbering: ##STR4##

As drawn hereinafter the formulas represent a particular opticallyactive isomer having the same absolute configuration as PGE₁ obtainedfrom mammalian tissues.

In the formulas, broken line attachments to the cyclopentane ring orside chain indicate substituents in alpha configuration, i.e. below theplane of the ring or side chain. Heavy solid line attachments indicatesubstituents in beta configuration, i.e. above the plane.

For background on prostaglandins, see for example Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968). For related compounds see Pace-Asciak etal., Biochem. 10, 3657 (1971). Related compounds are described in apublication on 6-keto-prostaglandin F₁α by Pace-Asciak, J. Am. Chem.Soc. 98, 2348 (1976) and a publication on "PGX"(6,9α-oxido-9α,15α-dihydroxyprosta-(Z)5, (E)13-dienoic acid) by E. J.Corey et al., J. Am. Chem. Soc. 99, 20006 (1977).

Some of the compounds of this invention may be regarded as analogs ofprostacyclin and prostacyclin-type compounds.

Prostacyclin, an organic compound related to prostaglandins, is(5Z)-9-deoxy-6,9α-epoxy-Δ⁵ -PGF₁ and is represented by the formula##STR5## For its synthesis and structure see for example R. A. Johnsonet al. J. Am. Chem. Soc. 99, 4182 (1977) and Prostaglandins 12, 915(1976), and E. J. Corey et al., cited above. For some of its biologicalproperties and uses see the references cited in the Johnson references.Prostacyclin is referred to as "PGl₂ ", see Anonymous, Prostaglandins13, 375 (1977).

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel products havingpharmacological activity. It is a further purpose to provide processesfor preparing these products and their intermediates.

Accordingly, there is provided a compound of the formula: ##STR6## or amixture comprising that compound and the enantiomer thereof wherein R₂₀is ##STR7## wherein L is (1) --(CH₂)_(d) --C(R₂)₂ --

(2) --CH₂ --O--CH₂ --Y-- or

(3) --CH₂ CH═CH--

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being thesame or different with the proviso that one R₂ is not methyl when theother is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein Q is ##STR8## wherein R₈ is hydrogen or alkyl of one to 4 carbonatoms, inclusive, wherein R₁ is

(1) --COOR₃

(2) --CH₂ OH

(3) --CH₂ N(R₉)(R₁₈) ##STR9## wherein R₃ is (a) hydrogen, (b) alkyl ofone to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbonatoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e)phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl of oneto 4 carbon atoms, inclusive, ##STR10## wherein R₁₀ is phenyl,p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or2-naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or (n) apharmacologically acceptable cation, wherein R₉ is hydrogen, methyl, orethyl, and R₁₈ is hydrogen, alkyl of one to 4 carbon atoms, inclusive,aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is ##STR11## wherein C_(g) H_(2g) is alkylene of one to 9carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in thechain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₈ arehydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, beingthe same or different, with the proviso that one of R₅ and R₆ is fluoroonly when the other is hydrogen or fluoro and the further proviso thatneither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z representsan oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valencebond or alkylene of one to 9 carbon atoms, inclusive, with one to 6carbon atoms, inclusive between CR₅ R₆ -- and the phenyl ring; wherein Tis alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, and s is zero, one, 2 or 3, with the proviso that notmore than two T's are other than alkyl and when s is 2 or 3 the T's areeither the same or different; and

wherein X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C═C-- or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

In formula IV as used herein, attachment to R₂₀ and R₂₁ corresponds tobonds to the cyclopentane ring at the C-8, C-9, and C-12 positionsfollowing prostaglandin nomenclature, thus:

Within the scope of the prostaglandin derivatives described herein thereare represented

(a) PGF.sub.α compounds when R₂₀ is ##STR13## (b) 11β-PGF.sub.αcompounds when R₂₀ is ##STR14## (c) 11-Deoxy-11-keto-PGF.sub.α compoundswhen R₂₀ is ##STR15## (d) 11-Deoxy-11-methylene-PGF.sub.α compounds whenR₂₀ ##STR16## (e) 11-Deoxy-PGF₆₀ compounds when R₂₀ is ##STR17## (f)11-Deoxy-10,11-Didehydro-PGF.sub.α compounds when R₂₀ is ##STR18## (g)11-Deoxy-11-hydroxymethyl-PGF.sub.α compounds when R₂₀ is ##STR19##

For those compounds of formula IV wherein Q is ##STR20## i.e. whereinthe C-15 hydroxyl group is attached to the side chain in alphaconfiguration, the configuration at C-15 is identical with that of thenaturally occuring prostaglandins such as PGE₁ obtained from mammaliantissues. The 15-epimer compounds are represented by formula IV when Q is##STR21## and are identified variously as "15-epi" or "15β" or "15R" bythe appropriate prefix in the name. As is known in the art, "R" and "S"designations depend on the neighboring substituents. See R. S. Cahn, J.Chem. Ed. 41, 116 (1964).

I claim:
 1. A 5E compound of the formula ##STR22## wherein W₁ isα--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂OH:β--H;wherein L is(1) --(CH₂)_(d) --C(R₂)₂, (2) --CH₂ --O--CH₂ --Y--,or (3) --CH₂ CH═CH--, wherein d is zero to 5, R₂ is hydrogen, methyl, orfluoro, being the same or different with the proviso that one R₂ is notmethyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or--(CH₂)₂ --, wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OHwherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,wherein R₃ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms,inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d)aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenylsubstituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms,inclusive, (g) p-[p-(acetamido)benzamido]phenyl, (h) p-benzamidophenyl,(i) p-acetamidophenyl, (j) p-phenylurea, (k) p-benzaldehydesemicarbazone, (l) β-naphthyl, (m) CH(R₁₁)--CO--R₁₀, wherein R₁₀ isphenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl,or 2 naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or(n) apharmacologically acceptable cation; wherein X is(1) trans--CH═CH--, (2)cis--CH═CH--, (3) --C═C--, or (4) --CH₂ CH₂ --; including the loweralkanoates thereof.
 2. A 5Z compound of the formula ##STR23## wherein W₁is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, α--CH₂OH:β--H;wherein L is(1) --(CH₂)_(d) --C(R₂)₂, (2) --CH₂ --O--CH₂ --Y--,or (3) --CH₂ CH═CH--, wherein d is zero to 5, R₂ is hydrogen, methyl, orfluoro, being the same or different with the proviso that one R₂ is notmethyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or--(CH₂)₂ --, wherein Q is oxo, α--H:β--H, α--OH:β--R₈ or α--R₈ :β--OHwherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,wherein R₃ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms,inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusvie, (d)aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenylsubstituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms,inclusive, (g) p-[p-(acetamido)benzamido]phenyl, (h) p-benzamidophenyl,(i) p-acetamidophenyl, (j) p-phenylurea, (k) p-benzaldehydesemicarbazone, (l) β-naphthyl, (m) CH(R₁₁)--CO--R₁₀, wherein R₁₀ isphenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl,or 2 naphthyl, and wherein R₁₁ is hydrogen or benzoyl, or(n) apharmacologically acceptable cation; wherein X is(1) trans--CH═CH--, (2)cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --; including the loweralkanoates thereof.
 3. (5Z)-9-Deoxy-6,9α-epoxymethano-Δ⁵-17,18-cisdidehydro-PGF₁, sodium salt, or(5Z)-9-deoxy-6,9α-epoxymethano-Δ⁵ -17,18-cis-didehydro-PGF₁, methylester, compounds according to claim
 2. 4. A compound according to claim1 or 2, wherein W₁ is α--H:β--OH.
 5. A compound according to claim 1 or2, wherein W₁ is oxo.
 6. A compound according to claim 1 or 2, whereinW₁ is methylene.
 7. A compound according to claim 1 or 2, wherein W₁ isα--H:β--H.
 8. A compound according to claim 1 or 2, wherein W₁ is α--CH₂OH:β--H.
 9. A compound according to claim 1 or 2, wherein W₁ isα--OH:β--H.
 10. A compound according to claim 9, wherein L is--(CH₂)_(n) --, n being 3, 4, or 5, wherein Q is oxo or α--OH:β--R₈ andwherein R₈ is hydrogen, methyl, or ethyl.
 11. A compound according toclaim 10, wherein X is --C.tbd.C--.
 12. A compound according to claim10, wherein X is --CH₂ CH₂ --.
 13. A compound according to claim 10,wherein X is trans--CH═CH--.
 14. A compound according to claim 13,wherein R₃ is p-substituted phenyl.
 15. A compound according to claim13, wherein R₃ is CH(R₁₁)--CO--R₁₀.
 16. A compound according to claim13, wherein R₃ is hydrogen, alkyl of one to 12 carbon atoms, inclusive,or a pharmacologically acceptable cation.
 17. A compound according toclaim 13, wherein R₃ is hydrogen, methyl, or a pharmacologicallyacceptable cation.